Process for making substituted pyrazoles

ABSTRACT

This invention relates to a novel process of preparing selected 5-substituted pyrazoles useful as p38 kinase and COX-2 inhibitors.

This application is a division of U.S. patent application Ser. No. 09/633,726 filed Aug. 7, 2000 now U.S. Pat. No. 6,242,613 which is a division of U.S. patent application Ser. No. 09/422,971 filed Nov. 18, 1999, now U.S. Pat. No. 6,143,892 which claims priority to U.S. Provision Application No. 60/109,177 filed Nov. 20, 1998.

FIELD OF THE INVENTION

This invention relates to the preparation of selected substituted heterocycles that are useful for the treatment of inflammatory diseases. In particular, the application discloses a method for the preparation of a number of substituted heterocycles that are p38 kinase and COX-2 inhibitors. The heterocycles described herein may be useful for the treatment of other disease states.

RELATED ART

Dithietanes have previously been prepared from selected 1,3-dicarbonyl compounds. These so-called active methylene compounds include esters of malonic acid, beta-keto esters, and 1,3-diketones. [(1) Katagiri, N.; Ise, S.; Watanabe, N.; Kaneko, C., Chem. Pharm. Bull. 1990, 12, 3242-3248. (2) Okajima, N.; Okada, Y., J. Heterocyclic Chem. 1990, 27, 567-574.] Selected dithioles derived from esters of malonic acid have been described as inhibitors of cancer metastasis. [Onaka, S.; Gokou, S. Japanese Patent Application JP 10212239 1998. Certain (1,2,4-triazolyl)ketene S,S-acetals have been previously reported to react with hydrazine to afford pyrazolyl-1,2,4-triazoles. [Huang, Z. N.; Li, Z. M., Synth. Commun. 1996, 26, 3115-3120.] Condensation of selected cyclic alpha-oxo-alpha-(1,2,4-triazol-1-yl)ketene N,S-acetals with hydrazine afforded 5-mercaptoalkylamino- and 5-anilinoalkylthiopyrazolyl-1,2,4-triazoles. [(1) Huang, Z. N.; Li, Z. M., Heterocycles 1995, 41, 1653-1658.] Historically, 3-amino-pyrazoles have been prepared by a sulfur extrusion rearrangement from 6H-1,3,4-thiadiazine derivatives in the presence of base. [(1) Beyer, H.; Honeck, H.; Reichelt, L., Justus Liebigs Ann. Chem. 1970, 741, 45. (2) Schmidt, R. R.; Huth, H., Tetrahedron Lett., 1975, 33. (3) Pfeiffer, W. D.; Dilk, E.; Bulka, E., Synthesis, 1977, 196-198.] This experimental protocol normally works adequately for the preparation of simple 3-amino-4-pyrazoles. The 6H-1,3,4-thiadiazine derivatives are in turn prepared by the condensation of alpha-chloroketones with thiosemicarbazides. This in turn necessitates preparing both the requisite alpha-chloroketone and thiosermicarbazide. In general, the aforementioned methodology was not useful for the preparation of the anti-inflammatory pyrazoles of the present invention. The known literature methods for the preparation of pyrazoles described above suffered from poor chemical yields and often gave mixtures of products that necessitated a careful chromatographic separation. In a number of instances, no desired pyrazole at all could be obtained using the methods disclosed in the literature. The present method has the advantage of being more direct (fewer steps) and provides the desired pyrazoles in significantly higher yield and with higher purity. In addition, the present method has the added advantage that it does not rely on the preparation of unstable alpha-chloroketones. Frequently the alpha-chloroketones suffered de-chlorination upon treatment with thiosemicarbazides.

SUMMARY OF THE INVENTION

This invention encompasses a process for the preparation of selected substituted pyrazole derivatives of the Formula A and B useful for the treatment of inflammatory diseases, wherein Y is SR₆, NR₄R₅, or OR₆.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses a process for making a compound of Formula Ia or Ib

wherein:

R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and a 5 or 6 membered heterocycle substituted with one or more substituents selected from the group consisting of C₁₋₃ alkyl, halo, OH, O-alkyl, cyano, CF₃, OCF₃ and substituted phenyl wherein the substituents are selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl, alkenyl, and alkynyl;

R₂ is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl optionally substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino, and dialkylamino;

R₃ is selected from the group selected from hydrogen, alkyl, and phenyl, wherein all but hydrogen may optionally be substituted by one or more of the group consisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, and SO₂NH₂;

R₄ is selected from the group consisting of alkyl, phenyl, cycloalkyl and heterocyclyl optionally substituted by one or more of the group consisting of OH, NH₂, SH, O-alkyl, NHR₇, N(R₇)₂, alkoxycarbonyl, acyl and halo;

R₅ is selected from the group consisting of alkyl, phenyl, cycloalkyl and heterocyclyl optionally substituted by one or more of the group consisting of OH, NH₂, SH, S-alkyl, O-alkyl, NHR₇, N(R₇)₂, CO₂H, halo, alkoxycarbonyl, acyl, heterocyclyl, cycloalkyl, heterocycloalkyl, and heterocyclyl;

R₄ and R₅ taken together may form a ring selected from the group consisting of morpholine, aziridine, thiomorpholine, piperidine, piperazine, and N′-piperazine;

R₇ is selected from the group consisting of alkyl and cycloalkyl;

comprising:

reacting an organometallic reagent of the formula R₂CH₂M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula Ic;

treating the ketone of Formula Ic with a mixture of carbon disulfide and dihalomethane such as dibromomethane or iodochloromethane in the presence of a base and a solvent to produce the dithietane derivative of Formula Id;

reacting the dithietane derivative of Formula Id with an amine of formula R₄—NH—R₅ to produce the thioamide of Formula Ie, If, or Ig;

condensing the thioamide of Formula Ie, If or Ig with hydrazine or substituted hydrazine.

In another embodiment of the invention is the process of making compounds of Formula IIa or IIb

wherein

R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6 membered heterocycle substituted with one or more substituents selected from the group consisting of C₁₋₃ alkyl, halo, OH, O-alkyl, cyano, CF₃, OCF₃, and substituted phenyl wherein the substituents are selected from one or more of the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl, alkenyl, and alkynyl;

R₂ is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl optionally substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino and dialkylamino;

R₃ is selected from the group selected from hydrogen, alkyl, and phenyl wherein all but hydrogen may be substituted by one or more of the group consisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, and SO₂NH₂;

R₆ is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl and heterocyclyl which may be optionally substituted by one or more of the group consisting of phenyl, substituted phenyl, alkoxycarbonyl, acyl, halo, OH, NH₂, NHR₃, N(R₃)₂, and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring;

comprising:

reacting an organometallic reagent of the formula R₂CH₂M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula Iic;

treating the ketone of Formula IIc with a mixture of carbon disulfide and dihalo methane such as dibromomethane or iodochloromethane in the presence of a base and a solvent to produce the dithietane derivative of Formula IId;

reacting the dithietane derivative of Formula IId with NaOR₆ to produce Formula IIe;

condensing Formula IIe with hydrazine or substituted hydrazine.

In another embodiment of the invention is the process of making compounds of Formula IIIa or IIIb

wherein:

R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6 membered heterocycle substituted with one or more of the substituents selected from the group consisting of alkyl, halo, OH, O-alkyl, cyano, CF₃, OCF₃, and substituted phenyl wherein the substituents are selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl, alkenyl, and alkynyl;

R₂ is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of one or more hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino, and dialkylamino;

R₃ is selected from the group selected from hydrogen, alkyl, phenyl of which all but hydrogen may be optionally substituted by one or more of the group consisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, and SO₂NH₂;

R₆ is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally substituted by one or more of the group consisting of phenyl, substituted phenyl, halo, alkoxycarbonyl, acyl, OH, NH₂, NHR₃, N(R₃)₂, and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring;

comprising:

reacting an organometallic reagent of the formula R₂CH₂M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula IIIc;

treating the ketone of Formula IIIc with a mixture of carbon disulfide and dihalomethane such as iodochloromethane or dibromomethane in the presence of a base and a solvent to produce the dithietane derivative of Formula IIId;

reacting the dithietane derivative of Formula IIId with R₃NHNH₂ to produce a heterocycle of the formula IIIe or IIIf and their tautomers;

reacting the heterocycle of the formula IIIe or IIIf with an activated form of R₆ in the presence of a base and a solvent.

The term “alkyl”, alone or in combination, means an acyclic alkyl radical containing from 1 to about 10, or from 1 to about 8 carbon atoms or 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.

The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, or from about 2 to about 8 carbon atoms or 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted. Examples of suitable alkenyl radicals include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, or about 2 to about 8 carbon atoms or 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term “cyano” radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.

The term “halo” means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term “haloalkenyl” denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.

The term “heterocyclyl” embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 7-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-pyridyl, 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5-to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl” group may have 1 to 3 substituents as defined below, Heterocyclic radicals include five to ten membered fused or unfused radicals. Non-limiting examples of heterocyclic radicals include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazonyl, quinolinyl, tetraazolyl, and the like.

The term “cycloalkyl” embraces radicals having three to ten carbon atoms. Cycloalkyl radicals are “lower cyclonlkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. Cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl.

The term “cycloalkenyl” embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Cycloalkenyl radicals are “lower cycloalkenyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “halocycloalkyl” embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. Halocycloalkyl radicals are “lower halocycloalkyl” radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term “halocycloalkenyl” embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.

The term “halocycloalkoxy” also embraces cycloalkoxy radicals having one or more halo radicals attached to the cycloalkoxy radical, that is, to form monohalocycloalkoxy, dihalocycloalkoxy, and polycycloalkoxy radicals.

The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Alkylthio radicals are “lower alkylthio” radicals having one to six carbon atoms. An example of “lower alkylthio” is methylthio (CH₃—S—). The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(═O)— atom.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term “alkoxyalkyl” also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. Alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.

The term “substituted phenyl” embraces a phenyl moiety substituted at one or more carbons with one or more suitable substituent. Said substituents include alkyl, alkenyl, alkynyl, O-alkyl, S-alkyl, O-alkenyl, S-alkenyl, halo, cyano, CF₃, OCF₃, SO₂NH₂, SO₂CH₃, OH, NH₂, N, S, O, and the like.

Scheme 1 shows a process for synthesis of selected 5-amino-pyrazoles. Treatment of 1 with a base such as sodium bis(trimethylsilyl)amide generates the corresponding organometallic. This organometallic reagent is then treated with an ester 2 in a suitable solvent such as tetrahydrofuran to afford the desired ketone 3. Treatment of ketone 3 with a mixture of carbon disulfide, dihalomethane, and a base such as potassium carbonate in a suitable solvent such as acetone provides the key dithietane compound 4. The dithietane compound 4 may then be reacted with an appropriate amine with or without heating in an acceptable solvent such as toluene or acetonitrile to make the thioamide compound 5. Thioamide compound 5 is treated with a mono-substituted hydrazine (6) or hydrazine (6, R═H) in an appropriate solvent such as tetrahydrofuran or an alcohol with or without heating to produce pyrazoles 7 and 8. In the case of hydrazine (6, R═H) the pyrazoles (7 and 8, R₃═H) thus produced are tautomers.

The dithietane 4 is added to a solution of a sodium or potassium alkoxide in THF. The alkoxide may be generated by treating an alcohol, in THF, with a suitable base, such as sodium hydride, NaHMDS, or KHMDS. The reaction mixture is allowed to stir from 4 to 72 hours at room temperature. The resulting thionoester 9 is allowed to react with hydrazine, or its hydrate, in ethanol, methanol, or THF at room temperature for 2-18 hours to generate the pyrazole products 10.

To the dithietane 4 in toluene is added an amine, such as thiomorpholine and heated from 80-110° C. The resulting thioamide 11 may be isolated or used directly in the next reaction step. To the thioamide in THF is added a suitable base, such as potassium t-butoxide and the resulting thiol anion alkylated with iodomethane. The resulting intermediate 12 can be cyclized with hydrazine, in a solvent, such as THF or ethanol, to generate the pyrazole 13.

The dithietane 4 in a suitable solvent, such as THF or ethanol, is allowed to react with hydrazine, or its hydrate, at room temperature up to the reflux temperature of the solvent to generate the thiopyrazole 14. The thiol group may be alkylated with a variety of alkylating agents, such as alkyl halides or Michael acceptors, including; methyl chioroacetate, ethyl acrylate, and henzyl bromide, in the presence of a suitable base such as potassium carbonate, sodium ethoxide or triethylamine in a solvent such as DMF or ethanol to generate the desired pyrazoles 15.

Pyrazoles, such as 16, containing acid labile amine protecting groups may be treated with a suitable acid catalyst, such as TFA in dichloromethane or HCl in ethanol or dioxane. The resulting amine 17 can then be acylated or alkylated in a straightforward fashion using a suitable base, such as potassium carbonate or triethylamine, with a reagent, such as for example; acetyl chloride or methyl iodide. In addition, N-methylation can be performed directly, using formaldehyde and formic acid in ethanol/water at reflux to give the desired pyrazoles 18.

Pyrazoles containing base labile esters, such as 19, may be treated with a suitable base, such as, NaOH to generate the free acid 20. The resulting acid can then aminated in a straightforward fashion using a suitable coupling reagent, such as EDC or TBTU, with or without catalysts, such as HOBt or N-hydroxysuccinimide, and an appropriate amine. In addition, amidation can be performed directly, by treating the methyl ester with an appropriate amine, for example N-methylpiperazine, in a suitable solvent such as DMF or methanol, at a temperature from room temperature up to reflux to generate the desired pyrazoles 21.

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the preceding schemes or the following Examples are also contemplated.

The starting materials which are required for the above processes herein described are known in the literature or can be made by known methods from known starting materials.

EXAMPLE 1

1-[5-(3-Tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine

Step 1

Preparation of 1-tolyl-2-(4-pyridyl)ethanone

Methyl 3-methylbenzoate (6.0 g, 40 mmol), tetrahydrofuran (50 mL), and 4-picoline (4.1 g, 44 mmol) were stirred at −78° C. under an atmosphere of nitrogen. Sodium bis(trimethylsilyl)amide 1.0 M in THF (88 mL, 88 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stir for 16 h when it was poured into saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated. The product was recrystallized from ethyl acetate/hexane to yield a light yellow solid (5.7 g, 67%): mp 118.0-119.0° C. ¹H NMR (acetone-d₆/300 MHz) 8.50 (m, 2H), 7.90 (m, 2H), 7.44 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H), 2.41 (s, 3H). ESHRMS m/z 212.1067 (M+H, C₁₄H₁₃NO requires 212.1075).

Anal. Calc'd for C₁₄H₁₃NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.54; H, 6.30; N, 6.56.

Step 2

Preparation of 1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridyl)ethanone

1-Tolyl-2-(4-pyridyl)ethanone (4.22 g, 20 mmol), acetone (100 mL), potassium carbonate (8.3 g, 60 mmol), carbon disulfide 4.56 g, 60 mmol), and dibromomethane (1.0.43 g, 60 mmol) were stirred at room temperature for 16 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over magnesium sulfate and concentrated. This crude material was purified by either flash column chromatography eluting with ethyl acetate:hexane or crystallization from ethyl acetate/hexane to yield a yellow solid (4.8 g, 80%): mp 178.6-179.2° C. ¹H NMR (acetone-d₆/300 MHz) 8.47 (m, 2H), 7.08 (m, 6H), 4.37 (s, 2H), 2.21 (s, 3H). ESHRMS m/z 300.0521 (M+H, C₁₆H₁₄NOS₂ requires 300.0517).

Anal. Calc'd for C₁₆H₁₃NOS₂: C, 64.18; H, 4.38; N, 4.68. Found: C, 64.08; H, 4.25; N, 4.62.

Step 3

Preparation of 1-[3-(3-tolyl)-3-oxo-2-(4-pyridyl)-1-thiopropyl]-4-methylpiperazine

1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridyl)ethanone (3.0 g, 10 mmol), N-methylpiperazine (5.0 g, 50 mmol), and toluene (50 mL) were heated to reflux using a Dean-Stark apparatus for 1 to 3 h. The reaction was allowed to cool to room temperature and was concentrated to dryness under high vacuum. This thick, oily material was crystallized from ethyl acetate/hexane (2.9 g, 82%): mp 124.8-125.8° C. ¹H NMR (acetone-d₆/300 MHz) 8.57 (m, 2H), 7.75 (m, 2H), 7.54 (m, 2H), 7.37 (m, 2H) 6.54 (s, 1H), 4.27 (m, 2H), 4.19 (m, 1H), 3.83 (m, 1H), 2.47-2.28 (m, 6H), 2.22 (s, 3H), 2.17 (m, 1H). ESHRMS m/z 354.1669 (M+H, C₂₀H₂₄N₃OS requires 354.1640).

Anal. Calc'd for C₂₀H₂₃N₃OS: C, 67.96; H, 6.56; N, 11.89. Found: C, 67.79; H, 6.66; N, 11.88.

Step 4

Preparation of 1-[5-(3-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine

1-[3-(3-tolyl)-3-oxo-2-(4-pyridyl)-1-thiopropyl]-4-methylpiperazine (1.06 g, 3 mmol), tetrahydrofuran (50 mL), and hydrazine (15 mL, 15 mmol, 1.0 M in THF were stirred at room temperature for 16 h. A white solid was collected by filtration.

Purification when necessary was by trituration or recrystallization (0.98 g, 97%): mp 261.9-262.0° C. ¹H NMR (DMSO-d₆/300 MHz) 12.6 (brs, 1H), 8.42 (m, 2H), 7.2 (m, 4H), 7.12 (s, 1H), 7.0 (m, 1H), 2.86 (m, 4H), 2.34 (m, 4H) 2.25 (s, 3H), 2.16 (s, 3H). ESHRMS m/z 334.2049 (M+H, C₂₀H₂₄N₅ requires 334.2032).

Anal. Calc'd for C₂₀H₂₃N₅: C, 72.04; H, 6.95; N, 21.00. Found: C, 71.83; H, 7.06; N, 20.83.

EXAMPLE 2

Step 1

1-(4-chlorophenyl)-2-(4-pyridyl)ethanone was prepared according to the procedure used in example 1, step 1, Yield: 74%, yellow solid, mp 95.5-97.3° C. ¹H-NMR (DMSO-d₆/300 MHz) 8.57 (br d, 2H), 7.92 (d, 2H), 7.46 (d, 2H), 7.20 (d, 2H), 4.28 (s, 2H). ESLRMS m/z 232 (M+H).

Step 2

To a solution of 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone (70.0 g, 0.3 mol), dibromomethane (200 mL) and carbon disulfide (25.9 g, 0.34 mol) in acetone (800 mL) was added potassium carbonate (83.0 g, 0.6 mol). The reaction mixture was stirred at room temperature for 24 h. An additional two equivalents of potassium carbonate and one equivalent of carbon disulfide was added and the stirring was continued for another 24 h. Solvent was removed and the residue was partitioned between dichioromethane and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was stiffed with 1 L of a mixture of ethyl acetate and ether (1:9) to give 78.4 g, 82% of pure product as a yellow solid, mp 185.3-185.4° C. ¹H NMR (acetone-d₆/300 MHz) 8.49 (m, 2H), 7.31 (m, 4H), 7.09 (m, 2H), 4.39 (s, 2H). ESHRMS m/z 319.9981 (M+H, C₁₅H₁₁ClNOS₂ requires 319.9971).

Anal. Calc'd for C₁₅H₁₀ClNOS₂: C, 56.33; H, 3.15; N, 4.38. Found: C, 56.47; H, 3.13; N, 4.44.

EXAMPLE 3

Prepared by the method described in Example 1, steps 1 and 2. mp 164.0-165.0° C. ¹H NMR (acetone-d₆/300 MHz) 8.49 (m, 2H), 7.25 (m, 2H), 7.0 (m, 3H), 4.38 (s, 2H), 2.24 (s, 3H). ESHRMS m/z 334.0130 (M+H, C₁₆H₁₂ClNOS₂ requires 334.0127).

Anal. Calc'd for C₁₆H₁₂ClNOS₂: C, 57.56; H, 3.62; N, 4.20. Found: C, 57.68; H, 3.67; N, 4.17.

EXAMPLE 4

Prepared by the method described in Example 1, steps 1 and 2. mp 126.5-126.6° C. ¹H NMR (acetone-d₆/300 MHz) 8.40 (m, 2H), 7.17 (m, 2H), 7.0 (m, 4H), 4.39 (s, 2H), 2.85 (s, 3H). ESHRMS m/z 300.0483 (M+H, C₁₆H₁₄NOS₂ requires 300.0517).

Anal. Calc'd for C₁₆H₁₃NOS₂: C, 64.18; H, 4.38; N, 4.68. Found: C, 64.05; H, 4.27; N, 4.59.

EXAMPLE 5

Prepared by the method described in Example 1, steps 1 and 2. mp 159.6-159.7° C. ¹H NMR (acetone-d₆/300 MHz) 8.52 (m, 2H), 7.6 (m, 1H), 7.50 (s, 1H), 7.21 (m, 2H), 7.13 (m, 2H), 4.40 (s, 2H). ESHRMS m/z 363.9503 (M+H, C₁₅H₁₁BrNOS₂ requires 363.9465).

Anal. Calc'd for C₁₅H₁₀BrNOS₂: C, 49.46; H, 2.77; N, 3.84. Found: C, 49.51; H, 2.68; N, 3.74.

EXAMPLE 6

Prepared by the method described in Example 1, steps 1 and 2. mp 198.8-198.9° C. ¹H NMR (acetone-d₆/300 MHz) 8.45 (m, 2H), 7.05 (m, 3H), 6.95 (m, 1H), 6.82 (m, 1H), 4.29 (s, 2H), 2.14 (s, 3H), 2.08 (s, 3H). ESHRMS m/z 314.0691 (M+H, C₁₇H₁₆OS₂ requires 314.0673).

EXAMPLE 7

Prepared by the method described in Example 1, steps 1 and 2. mp 182.6-183.0° C. ¹H NMR (acetone-d₆/300 MHz) 8.50 (m, 2H), 7.42 (d, 2H, J=8.5 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.10 (m, 2H), 4.40 (s, 2H). ESHRMS m/z 370.0173 (M+H, C₁₆H₁₁F₃NO₂S₂ requires 370.0183).

EXAMPLE 8

Prepared by the method described in Example 1, steps 1 and 2. mp 193.3-193.4° C. ¹H NMR (acetone-d₆/300 MHz) 8.49 (m, 2H), 7.69 (d, 2H, J=8.2 Hz), 7.46 (d, 2H, J=8.2 Hz), 7.01 (m, 2H), 4.43 (s, 2H). ESHRMS m/z 311.0327 (M+H, C₁₆H₁₁N₂OS₂ requires 311.0313).

EXAMPLE 9

Prepared by the method described in Example 1, steps 1 and 2. mp 191.5-192.5° C. ¹H NMR (CDCl₃/300 MHz) 8.55 (dd, 2H, J=4.6, 1.6 Hz), 7.4 (m, 1H), 7.09-7.03 (m, 3H), 6.67 (d, 1H, J=8.7 Hz), 4.17 (s, 211), 3.86 (s, 3H). ESHRMS m/z 350.0090 (M+H, C₁₆H₁₃ClNO₂S₂ requires 350.0076).

Anal. Calc'd. for C₁₆H₁₂ClNO₂S₂: C, 54.93; H, 3.60; N, 4.00; Cl, 10.13; S, 18.33. Found: C, 54.74; 11,3.60; N, 3.89; Cl, 10.45; S, 18.32.

EXAMPLE 10

Prepared by the method described in Example 1, steps 1 and 2. mp 172.1-173.1° C. ¹H NMR (CDCl₃/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz), 7.23-7.21 (m, 4H), 7.04 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H), 1.25 (s, 9H). ESHRMS m/z 342.1004 (M+H, C₁₉H₂₀NOS₂ requires 342.0986).

Anal. Calc'd for C₁₉H₁₉NOS₂: C, 66.83; H, 5.61; N, 4.10; S, 18.78. Found: C, 66.97; H, 5.89; N, 4.02; S, 18.64.

EXAMPLE 11

Prepared by the method described in Example 1, steps 1 and 2. mp 203.0-204.1° C. ¹H NMR (CDCl₃/300 MHz) 8.52 (dd, 2H, J=4.4, 1.6 Hz), 7.29 (d, 1H, J=6.8 Hz), 7.28 (d, 1H, J=7.0 Hz), 7.05 (dd, 2H, J=4.4, 1.6 Hz), 6.70 (d, 1H, J=6.8 Hz), 6.69 (d, 1H, J=6.8 Hz), 4.17 (s, 2H), 3.79 (s, 3H). ESHRMS m/z 316.0475 (M+H, C₁₆H₁₄NO₂S₂ requires 316.0466).

Anal. Calc'd. for C₁₆H₁₃NO₂S₂: C, 60.93; H, 4.15; N, 4.44; S, 20.33. Found: C, 60.46; H, 4.17; N, 4.37; S, 19.84.

EXAMPLE 12

Prepared by the method described in Example 1, steps 1 and 2. mp 209.1-215.1° C. ¹H NMR (CDCl₃/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6 Hz), 7.20 (d, 2H, J=8.0 Hz), 7.03-6.99 (m, 4H), 4.18 (s, 2H), 2.30 (s, 3H). ESHRMS m/z 300.0517 (M+H, C₁₆H₁₄NOS₂ requires 300.0517).

Anal. Calc'd. for C₁₆H₁₃NOS₂: C64.18; H, 4.38; N, 4.69; S, 21.42. Found: C, 64.02; H, 4.62; N, 4.54; S, 21.24.

EXAMPLE 13

Prepared by the method described in Example 1, steps 1 and 2. mp 257.6-257.7° C. ¹H NMR (CDCl₃/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz), 7.57 (d, 2H, J=8.5 Hz), 7.27-6.99 (m, 4H), 4.18 (s, 2H). ESHRMS m/z 411.9348 (M+H, C₁₅H₁₁NIOS₂ requires 411.9327).

Anal. Calc'd. for C₁₅H₁₀NIOS₂: C, 43.81; H, 2.45; N, 3.41. Found: C, 43.71; H, 2.27; N, 3.41.

EXAMPLE 14

Prepared by the method described in Example 1, steps 1 and 2. mp 197.3-202.2° C. ¹H NMR (CDCl₃/300 MHz) 8.53(dd, 2H, J=4.4, 1.6 Hz), 7.26 (d, 2H, J=9.3 Hz), 7.09 (dd, 2H, J=4.4, 1.6 Hz), 6.43 (d, 2H, J=9.3 Hz), 4.14 (s, 2H), 2.97 (s, 6H). ESHRMS m/z 329.0789 (M+H, C₁₇H₁₇N₂OS₂ requires 329.0782).

Anal. Calc'd. for C₁₇H₁₆N₂OS₂: C, 62.17; H, 4.91; N, 8.53; S, 19.53. Found: C, 61.93; H, 5.12; N, 8.46; S,19.26.

EXAMPLE 15

Prepared by the method described in Example 1, steps 1 and 2. mp 176.6-176.7° C. ¹H NMR (CDCl₃/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz), 7.29-7.22 (m, 4H), 7.03 (dd, 2H, J=4.4, 1.6 Hz), 6.64 (dd, 1H, J=17.5, 10.9 Hz), 5.76 (d, 1H, J=17.7 Hz), 5.31 (d, 1H, J=10.9 Hz), 4.19 (s, 2H). ESHRMS 312.0513 (M+H, C₁₇H₁₄NOS₂ requires 312.0517).

Anal. Calc'd. for C₁₇H₁₃NOS₂: C, 65.56; H, 4.21; N, 4.50. Found: C, 65.75; H, 4.11; N, 4746.

EXAMPLE 16

Prepared by the method described in Example 1, steps 1 and 2. mp 174.8-175.0° C. ¹H NMR (CDCl₃/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6 Hz), 7.23-7.20 (m, 4H), 7.03 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H), 2.59 (q, 2H, J=7.6 Hz), 1.17 (t, 3H, J=7.7 Hz). ESHRMS m/z 314.0677 (M+H, C₁₇H₁₆NOS₂ requires 314.0673).

Anal. Calc'd. for C₁₇H₁₅NOS₂: C, 65.14; H, 4.82; N, 4.47. Found: C, 64.90; H, 4.62; N, 4.45.

EXAMPLE 17

Prepared by the method described in Example 1, steps 1 and 2. mp 167.1-167.5° C. ¹H NMR (CDCl₃/300 MHz) 8.52 (dd, 1H, J=4.4, 1.6 Hz), 7.33 (d, 1H, J=8.3 Hz), 7.02-7.00 (m, 3H), 6.87-6.83 (m, 1H), 4.19 (s, 2H), 2.28 (s, 3H). ESHRMS m/z 379.9577 (M+H, C₁₆H₁₃BrNOS₂ requires 379.9622).

Anal. Calc'd. for C₁₆H₁₂BrNOS₂: C, 50.80; H, 3.20; N, 3.70. Found: C, 50.69; H, 3.19;7 N, 3.71.

EXAMPLE 18

Prepared from Example 3 by the method described in Example 1, steps 3 and 4. mp 236.7-239.3° C. ¹H NMR (DMSO-d₆/300 MHz) 12.6 (brs, 1H), 8.45 (m, 2H), 7.41 (m, 1H), 7.26 (m, 3H), 7.0 (m, 1H), 2.86 (m, 4H), 2.35 (m, 4H), 2.27 (s, 3H), 2.16 (s, 3H). ESHRMS m/z 368.4653 (M+H, C₂₀H₂₃ClN₅ requires 368.1642).

EXAMPLE 19

Prepared from Example 4 by the method described in Example 1, steps 3 and 4. mp 244.0-244.2° C. ¹H NMR (acetone-d₆/300 MHz) 11.6 (brs, 1H), 8.35 (m, 2H), 7.35 (m, 2H), 7.25 (m, 4H), 3.05 (m, 4H), 2.47 (m, 4H), 2.25 (s, 3H), 2.00 (s, 3H). ESHRMS m/z 334.2018 (M+H, C₂₀H₂₄N₅ requires 334.2032).

Anal. Calc'd for C₂₀H₂₃N₅: C, 72.04; H, 6.95; N, 21.00. Found: C, 72.03; H, 7.00; N, 20.85.

EXAMPLE 20

Prepared from Example 5 by the method described in Example 1, steps 3 and 4. mp 222.5-223.4° C. ¹H NMR (acetone-d₆/300 MHz) 11.8 (brs, 1H), 8.51 (m, 2H), 7.55 (m 2H), 7.34 (m, 4H), 3.0 (m, 4H), 2.41 (m, 4H), 2.22 (s, 3H). ESHRMS m/z 398.0982 (M+H, C₁₉H₂₁BrN₅ requires 398.0980).

EXAMPLE 21

Prepared from Example 6 by the method described in Example 1, steps 3 and 4. mp 270.9-272.7° C. ¹H NMR (DMSO-d₆/300 MHz) 12.5 (brs, 1H), 8.41 (m, 2H), 7.24 (m, 2H), 7.26 (m, 3H), 7.10 (m, 2H), 6.92 (m, 1H), 2.86 (m, 4H), 2.38 (m, 4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H). ESHRMS m/z 348.2183 (M+H, C₂₂H₂₅N₅ requires 348.2188).

EXAMPLE 22

Prepared from Example 7 by the method described in Example 1, steps 3 and 4. mp 221.0-221.2° C. ¹H NMR (DMSO-d₆/300 MHz) 12.7 (brs, 1H), 8.45 (m, 2H), 7.38 (s, 4H), 7.24 (m, 2H), 2.86 (m, 4H), 2.34 (m, 4H), 2.16 (s, 3H). ESHRMS m/z 404.1698 (M+H, C₂₀H₂₁F₃N₅O requires 404.1698).

EXAMPLE 23

Prepared from Example 8 by the method described in Example 1, steps 3 and 4. mp>300° C. ¹H NMR (DMSO-d₆/300 MHz) 12.8 (brs, 1H), 8.47 (m, 2H), 7.83 (m, 2H), 7.42 (m, 2H), 2.88 (m, 4H), 2.39 (m, 4H), 2.20 (s, 3H). ESHRMS m/z 345.1848 (M+H, C₂₀H₂₁N₆ requires 345.1828).

EXAMPLE 24

Prepared from Example 9 by the method described in Example 1, steps 3 and 4. mp 272.7-276.4° C. ¹H NMR (DMSd₆/300 MHz) 8.44 (dd, 2H, J=4.6, 1.6 Hz), 7.32-7.13 (m, 5H), 3.84 (s, 3H), 2.90-2.85 (m, 4H), 2.38-2.35 (m, 4H), 2.16 (s, 3H). ESHRMS m/z 384.1580 (M+H C₂₀H₂₃ClN₅O requires 384.1591).

EXAMPLE 25

Prepared from Example 10 by the method described in Example 1, 3 and 4. mp 243.6-244.3° C. ¹H NM (DMSO-d₆/300 MHz) 8.44 (dd, 2H, J=4.6, 1.6, Hz), 7.40 (d, 2H, J=8.3 Hz), 7.28-7.18 (m, 4H), 2.90-2.85 (m, 4=H), 2.38-2.34 (m, 4H), 2.16 (s,3H), 1.26 (s, 9H). ESHRMS m/z 376.2491 (M+H, C₂₃H₃₀N₅ requires 376.2501).

EXAMPLE 26

Prepared from Example 11 by the method described in Example 1, steps 3 and 4. mp 259.0-260.2° C. ¹H NMR (DMSO-d₆/300 MHz) 8.53 (dd, 2H, J=4.4, 1.6 Hz), 7.24 (dd, 2H, J=4.4, 1.6 Hz), 7.18 (d, 2H, J=8.9 Hz), 6.94 (d, 2H, J=8.9 Hz), 3.75 (s, 3H), 2.90-2.85 (m, 4H), 2.39-2.35 (m, 4H), 2.16 (s, 3H). ESHRMS m/z 350.1991 (M+H, C₂₀H₂₄N₅O requires 350.1981).

Anal. Calc'd. for C₂₀H₂₃N₅O+3.93% H₂O: C, 66.04; H, 6.81; N, 19.25. Found: C, 66.01; H, 6.62; N, 19.32.

EXAMPLE 27

Prepared from Example 12 by the method described in Example 1, steps 3 and 4. mp 243.0-246.8° C. ¹H NMR (DMSO-d₆/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.24 (m, 6H), 2.91-2.86 (m, 4H), 2.40-2.35 (m, 4H), 2.29 (s, 3H), 2.16 (s, 3H). ESHRMS m/z 334.2041 (M+H, C₂₀H₂₄N₅ requires 334.2032).

Anal. Calc'd for C₂₀H₂₃N₅+4.09% H₂O: C, 69.10; H, 7.13; N, 20.14. Found: C, 69.10; H, 7.08; N, 20.13.

EXAMPLE 28

Prepared from Example 13 by the method described in Example 1, steps 3 and 4. mp 265.2-265.8° C. ¹H NMR (CD₃OD/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.76-7.74 (m, 2H), 7.41-7.39 (m, 2H), 7.08-7.05 (m, 2H), 3.08-3.04 (m, 4H), 2.61-2.58 (m, 4H), 2.35 (s, 3H). ESHRMS m/z 446.0847 (M+H, C₁₉H₂₁IN₅ requires 446.084169).

Anal. Calc'd. for C₁₉H₂₀IN₅+12.09% H₂O: C, 44.60; H, 5.39; N, 13.69. Found: C, 44.50; H, 4.56; N, 13.66.

EXAMPLE 29

Prepared from Example 15 by the method described in Example 1, steps 3 and 4. mp>300° C. ¹H NMR (CD₃OD/300 MHz) 8.49 (dd, 2H, J=4.6, 1.6 Hz), 7.47-7.44 (m, 4H), 7.26 (d, 2H, J=8.4 Hz), 6.75 (dd, J=17.7, 11.1 Hz), 5.83 (d, 1H, J=17.5 Hz), 5.28 (d, 1H, J=11.1 Hz), 3.07-3.03 (m, 4H), 2.58-2.53(m, 4H), 2.31 (s, 3H). ESHRMS m/z 346.2034 (M+H, C₂₁H₂₄N₅ requires 346.2032).

Anal. Calc'd. for C₂₁H₂₃N₅+2.83% H₂O: C, 70.95; H, 6.84; N, 19.70. Found: C, 70.97; H, 6.49; N, 19.54.

EXAMPLE 30

Prepared from Example 16 by the method described in Example 1, steps 3 and 4. mp 221.6-222.6° C. ¹H NMR (CD₃OD/300 MHz) 8.38 (dd, 2H, J=4.6, 1.6 Hz), 7.44-7.40 (m, 2H), 7.26-7.19 (m, 4H), 3.06-3.02 (m, 4H), 2.66 (q, 2H, J=7.5 Hz), 2.59-2.54 (m, 4H), 2.32 (s, 3H), 1.23 (t, 3H, J=7.5 Hz). ESHRMS m/z 348.2188 (M+H, C₂₁H₂₆N₅ requires 348.2188).

Anal. Calc'd for C₂₁H₂₅N₅+2.59% H₂O: C, 70.71; H, 7.35; N, 19.63. Found: C, 70.76; H, 7.40; N, 19.46.

EXAMPLE 31

Prepared from Example 17 by the method described in Example 1, steps 3 and 4. mp 294.7° C. decomp. ¹H NMR (CD₃OD/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.55 (d, 1H, J=8.2 Hz), 7.45-7.42 (m, 2H), 7.27-7.25 (m, 1H), 7.00-6.97 (m 2H), 3.08-3.03 (m, 4H), 2.59-2.54 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H). ESHRMS m/z 412.1124 (M+H, C₂₀H₂₃BrN₅ requires 412.1137).

EXAMPLE 32

To N-(2-hydroxyethyl)morpholine (363 uL, 3 mmol) in anhydrous THF (7 mL), under nitrogen, was added 1M sodium bis(trimethylsilyl)amide (3 ml, 3 mmol) in THF at ambient temperature. The reaction mixture was stirred for 15 minutes, then the dithietane of Example 2 (636 mg, 2 mmol) was added as a solid. The reaction mixture gradually became dark orange. After about 18 hours at ambient temperature, the reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted twice with ethyl acetate (30 mL). The organic solutions were combined and washed with saturated NaCl solution (20 mL), then dried (MgSO₄), filtered, and concentrated to an orange oil. The oil was taken up in MeOH (10 mL) and reconcentrated to remove any remaining ethyl acetate. The oil was then taken up in methanol (5 mL) and anhydrous hydrazine (69 uL) was added. The reaction mixture was allowed to stir at ambient temperature 18 hours, then quenched with saturated sodium bicarbonate solution (30 mL) and extracted twice with ethyl acetate (30 mL). The organic solutions were combined and washed with water (20 mL) and saturated NaCl solution (20 mL), then dried (MgSO₄), filtered, and concentrated to an orange semi-solid. The solid was triturated with acetonitrile (5 mL), collected by suction filtration, washed with acetonitrile and dried in-vacuo. Yield; off-white solid, 114 mg, 14.8%, mp 198.9-199.9° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.61 (br s, 1H), 8.41 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.33 (t, 2H), 3.54 (m, 4H), 2.70 (t, 2H), 2.44 (m 4H). ESHRMS m/z 385.1444 (M+H, C₂₀H₂₂ClN₄O₂ requires 385.1431).

EXAMPLE 33

The product was prepared in an analogous manner to that of Example 32, starting with 4-hydroxy-N-t-boc piperidine. Recrystallized from acetone/methanol. Yield; white solid 263 mg, 29%, mp 230.1-231.8° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.61 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.20 (d, 2H), 4.88 (m, 1H), 3.52 (m, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.65 (m, 2H), 1.39 (s, 9H).

Anal. Calc'd for C₂₄H₂₇ClN₄O₃: C, 63.36; H, 5.98; N, 12.31. Found: C, 63.34; H, 5.97; N, 12.22.

EXAMPLE 34

The product from Example 33 (130 mg, 0.28 mmol) was treated with conc. HCl (0.5 mL) in ethanol (5 mL) for 2 hours. The solvent was removed in-vacuo and the resulting residue dissolved in ethanol and reconcentrated twice. The resulting solid was triturated with acetonitrile to afford a white solid. Yield, 119 mg ,91%, trihydrochloride salt, mp 220.6-222.1° C. ¹H-NMR (DMSO-d₆/300 MHz) 13.25 (br s, 1H), 9.10 (br s, 2H), 8.67 (d, 2H), 7.75 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 5.04 (m, 1H, 3.17 (br d, 4H), 2.21 (m, 2H), 2.03 (m, 2H).

Anal. Calc'd for C₁₉H₁₉ClN₄O .03 HCl: C, 49.16; H, 4.78; N, 12.07. Found: C, 49.24; H, 4.72; N, 12.02.

EXAMPLE 35

The product was prepared in a manner analogous to Example 32 starting with (±)3-hydroxytetrahydrofuran. Recrystallized from ethanol. Yield; white crystalline solid, 57 mg ,8%, mp>300° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.65 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.18 (d, 2H), 5.28 (m, 1H), 3.86 (m, 2H), 3.82 (m, 1H), 3.75 (m, 1H), 2.26-2.01 (br m, 2H).

Anal. Calc'd for C₁₈H₁₆ClN₃O₂: C, 63.25; H, 4.72; N, 12.29. Found: C, 63.12; H, 4.51; N, 12.31.

EXAMPLE 36

The product was prepared in a manner analogous to Example 32 starting with p-methoxybenzyl alcohol. Yield; off-white solid, 252 mg, 21%, mp=229.1-229.2° C. ¹H-NMR (acetone-d₆/300 MHz) 11.62 (br s, 1H), 8.40 (br s, 2H), 7.76 (s, 2H), 7.39 (m, 4H), 7.30 (br s, 2H), 6.87 (d, 2H), 5.27 (s, 2H), 3.77 (s, 3H).

Anal. Calc'd for C₂₂H_(l8)ClN₃O₂.0.25 H₂O: C, 66.67; H, 4.70; N, 10.60. Found: C, 66.79; H, 4.95; N, 10.54.

EXAMPLE 37

The product was prepared in a manner analogous to Example 32 starting with N-Boc-ethanolamine. Recrystallized from ethyl acetate/methanol. Yield; white solid, 75 mg, 4%, mp>300° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.60 (br s, 1H), 8.38 (d, 2H), 7.53 (d, 2H), 7.38 (d, 2H), 7.22 (d, 2H), 7.02 (t, 1H), 4.20 (t, 2H), 3.34 (m, 2H), 1.36 (s, 9H). ESHRMS m/z 415.1551 (M+H, C₂₁H₂₄ClN₄O₃ requires 415.1537).

EXAMPLE 38

The example was prepared in a manner analogous to Example 32 starting with methanol. Yield; off-white solid, 119 mg, 14%, mp=265.3-265.3° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.61 (br s, 1H), 8.41 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.17 (d, 2H), 3.90 (s, 3H). ESHRMS m/z 286.0766 (M+H, C₁₅H₁₃ClN₃O requires 286.0747).

Anal. Calc'd for C₁₅H₁₂ClN₃O.0.25 H₂O: C, 62.08; H, 4.34; N, 14.48. Found: C, 62.24; H, 4.11; N, 14.16.

EXAMPLE 39

To the dithietane of Example 2 (638 mg, 2 mmol) in toluene (15 mL) was added thiomorpholine (800 uL, 8 uL). The reaction mixture was heated to reflux for 6 hours, then cooled to room temperature and diluted with toluene (20 mL). The reaction mixture was then extracted twice with water (20 mL) and brine (20 mL). The organic solution was dried (MgSO₄), filtered, and concentrated to an oil. Hexane was added to the residue and heated to reflux, then decanted. The oil became semi-solid. The semi-solid was dissolved in tetrahydrofuran (10 mL) and potassium t-butoxide 1M in THF (2 mL, 2 mmol) was added. This was followed by iodomethane (125 uL, 2 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with water (20 mL). The reaction mixture was extracted with ethyl acetate (2×30 mL). The organic layers were pooled, washed with brine (20 mL) and dried (MgSO ₄). Filtration and concentration produced an oil which was chased once with toluene to remove any ethyl acetate. The residue was dissolved in ethanol (10 mL) and hydrazine hydrate (97 uL, 2 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours then partitioned between ethyl acetate and saturated sodium bicarbonate solution (30 mL each). The layers were separated and the aqueous layer extracted again with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO₄). Filtration and concentration produced an orange residue which was triturated with acetonitrile to generate a tan solid. Yield: 295 mg, 43%, mp>300° C. ¹H NMR (DMSO-d₆/300 MHz) 12.70 (br s, 1H), 8.47 (d, 2H), 7.46 (d, 2H), 7.26 (m, 4H), 3.13 (m, 4H), 2.62 (m, 4H). ESHRMS m/z 357.0942 (M+H, C₁₈H₁₈ClN₄S requires 357.0941).

Anal. Calc'd for C₁₈H₁₇ClN₄S: C, 60.58; H, 4.80; N, 15.70. Found: C, 60.32; H, 4.96; N, 15.60.

EXAMPLE 40

The product of Example 33 (455 mg, 1.5 mmol) was combined with 98% formic acid (6 mL) and heated to 100 C. After 3 hours, 37% formaldehyde (1.22 mL, 15 mmol) was added and the reaction was heated for an additional 5 hours at 100 C. The reaction mixture was allowed to cool to room temperature and filtered. The solution was diluted with water (15 mL) and extracted once with ethyl acetate (30 mL). The aqueous solution was then basified with 2.5 N NaOH to pH 8. The cloudy mixture was then extracted twice with 1:1 THF:EtOAc (30 mL). The organic layers were pooled and washed once with brine (25 mL), dried (MgSO₄), filtered and concentrated to an oil which solidified on standing. The solid was triturated with acetonitrile and collected by suction filtration. The solid was suspended in ethanol:water 2:1 (15 mL) and 1 mL of conc. HCl was added. The solution was allowed to stir at room temperature for 1 hour, then filtered and concentrated. The residue was combined with ethanol (10 mL) and reconcentrated twice. The resulting solid was triturated with acetonitrile (10 mL) containing a small amount of ethanol (0.5 mL) to remove some colored impurities. The solid was collected by suction filtration, washed with acetonitrile and dried in-vacuo. Yield: 490 mg, 88%, mp 255.9-256.8° C. ¹H NMR (D₂O/DMSO-d₆/NaOD/300 MHz) 7.93 (d, 2H), 7.09 (s, 4H), 7.00 (d, 2H), 4.42 (m, 1H), 2.26 (br m, 2H,) 2.12 (br m, 2H), 1.92 (s, 3H), 1.68 (br m, 2H), 1.57 (br m, 2H). ESLRMS m/z 369 (M+H).

EXAMPLE 41

Step 1

A mixture of the dithietane from Example 2 (78.3 g, 0.24 mol) and 1-methylpiperazine (75.0 g, 0.73 mol) in 800 mL of toluene was heated to reflux for 2 h. Solvent and excess 1-methylpiperazine was removed under vacuum and the residue was triturated with a mixture was ethyl acetate and ether (1:3) to give 53.0 g of product as yellow crystals, 60%, mp 149-151° C.

Anal. Calc'd. for C₁₉H₂₀ClN₃OS: C, 61.03; H, 5.39; N, 11.24. Found: C, 60.74; H, 5.35; N, 11.14.

Step 2

To a suspension of the product from Step 1 (52.0 g, 0.14 mol) in 500 mL of dry tetrahydrofuran was added anhydrous hydrazine (8.9 g, 0.28 mol) dropwise. The reaction mixture was stirred at room temperature for 16 h. The pale yellow precipitate was filtered and recrystallized from hot methanol to give 30.2 g of the title compound as a white powder, 60%, mp 267-268° C.

Anal. Calc'd. for C₁₉H₂₀ClN₅: C, 64.49; H, 5.70; N, 19.79. Found: C, 64.89; H, 5.55; N, 19.99.

EXAMPLE 42

To 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (1.0 g, 4.7 mmol), in anhydrous THF (10 mL) was added a solution of 1M potassium t-butoxide in THF (10 mL, 10 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then carbon disulfide (0.31 mL, 5.1 mmol) was added. After several minutes, methyl iodide (0.64 mL, 10.3 mmol) was added and the reaction allowed to stir for 4 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (25 mL) and extracted twice with ethyl acetate (35 mL). The combined ethyl acetate layers were washed with water (25 mL) and brine (25 mL). The organic solution was dried (MgSO₄), filtered and concentrated to an orange oil. The oil solidified on standing to afford 1.4 g, 94%, of the expected product mp 80.2-82.1° C. ¹H-NMR (CDCl₃/300 MHz) 8.59 (d, 2H), 7.96 (m, 2H), 7.38 (m, 2H), 7.14 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H).

Anal. Calc'd for C₁₆H₁₄FNOS₂: C, 60.16; H, 4.42; N, 4.39; S, 20.08. Found: C, 59.89; H, 4.09; N, 4.31; S, 20.14.

EXAMPLE 43

The product was prepared in a manner analogous to Example 42 starting from 1-(4-chlorophenyl)-2-(4pyridyl)ethanone. Crude yield; 100%, mp 87.6-88.2° C. ¹H-NMR (CDCl₃/300 Mz) 8.60 (d, 2H), 7.87 (d, 2H), 7.44 (d, 2H), 7.37 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H). ESHRMS m/z 336.0297 (M+H, C₁₆H₁₄ClNOS₂ requires 336.0283).

Anal. Calc'd for C₁₆H₁₄ClNOS₂: C, 57.22; H, 4.20: N, 4.17. Found: C. 57-44; H, 3.97; N. 4.04.

EXAMPLE 44

To the product of Example 42 (1.4 g, 4.4 mmol) in ethanol (15 mL) was added 1M hydrazine in acetic acid (5 mL 5 mmol). The reaction was stirred at room temperature for 18 hours. No reaction had occurred, so additional hydrazine hydrate (1.08 mL, 22 mmol) was added and the reaction heated to reflux for 6 hours. The product began to precipitate from the reaction mixture. The reaction was cooled to room temperature and water was added to precipitate the product. The solid was collected by suction filtration and air dried to afford the crude desired pyrazole, 675 mg, 53%. The product was recrystallized from ethanol, 494 mg, mp 249.9-249.9° C. ¹H-NMR (DMSO-d₆/300 MHz) 13.51 (br s, 1H), 8.50 (d, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.16 (m, 2H), 2.43 (s, 3H). ESHRMS m/z 286.0807 (M+H, C₁₅H₁₃FN₃S requires 286.0814).

Anal. Calc'd for C₁₅H₁₂FN₃S: C, 63.14; H, 4.24; N, 14.73. Found: C, 63.01; H, 4.43; N, 14.81.

EXAMPLE 45

The product was made in an analogous manner to Example 44 starting with the product of Example 43. Yield; 750 mg, 33%, mp 250.2-250.2° C. ¹H NMR (DMSO-d₆/300 MHz) 13.57 (br s, 1H), 8.51 (m, 2H), 7.45 (br s, 2H), 7.32 (m, 2H), 7.17 (m, 2H), 2.43 (s, 3H). ESHRMS m/z 302.0537 (M+H, C₁₅H₁₃ClN₃S requires 302.0518).

Anal. Calc'd for C₁₅H₁₂ClN₃S: C, 59.70; H, 4.01; N, 13.92. Found: C, 59.56; H, 3.96; N, 13.96.

EXAMPLE 46

To the product of Example 44 (150 mg, 0.52 mmol) in ethanol (15 mL) was added ammonium persulfate (450 mg, 1.97 mmol). The reaction mixture was stirred at ambient temperature. After several hours an additional amount of ammonium persulfate (450 mg).was added. The reaction mixture was monitored by TLC (silica) using 5% methanol in dichloromethane as the eluting solvent. When the starting material had been consumed, the reaction mixture was quenched with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (2×25 mL). The ethyl acetate layers were combined, washed with brine (25 mL) and dried (MgSO₄). Filtration and concentration produced a white solid. The solid was triturated with diethyl ether, collected by suction filtration, and air dried to provide 150 mg, 96%, mp 262.9-262.9° C. of the desired sulfoxide. ¹H NMR (DMSO-d₆/300 MHz) 14.22 (br s, 1H), 8.56 (d, 2H), 7.42-7.23 (br m, 6H), 2.94 (s, 3H).

Anal. Calc'd for C₁₅H₁₂FN₃OS.0.25 H₂O: C, 58.91; H, 4.12; N, 13.74. Found: C, 58.88; H, 4.17; N, 13.39.

EXAMPLE 47

To the product of Example 44 (285 mg, 1 mmol) in ethanol (10 mL) was added potassium peroxymonosulfate (2.45 g, 4 mmol) and water (5 mL). The reaction mixture was stirred at ambient temperature. After 6 hours the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The ethyl acetate layers were combined, washed with brine (25 mL) and dried (MgSO₄). The ethyl acetate did not efficiently extract the product from the aqueous phase, so the aqueous layer was saturated with sodium chloride and extracted with acetonitrile (50 mL). The acetonitrile solution was dried (MgSO₄), filtered, and combined with the filtered ethyl acetate solution. The solvents were evaporated and the resulting solid was triturated with a small amount of acetonitrile, collected by suction filtration, and air dried to afford 203 mg, 64, %, mp 297.1−>300° C. ¹H NMR (DMSO-d₆/300 MHz) 14.37 (br s, 1H), 8.54 (m, 2H), 7.29 (m, 6H), 3.26 (s, 3H).

Anal. Calc'd for C₁₅H₁₂FN₃O₂S: C, 56.77; H, 3.81; N, 13.24. Found: C, 56.52; H, 4.03; N, 13.11.

EXAMPLE 48

The product was prepared in a similar manner to Example 1 starting from methyl 4-bromobenzoate. Obtained a white solid, mp 270.2-270.7° C. ¹H NMR (DMSO-d₆/300 MHz) 12.7 (br s, 1H), 8.47 (m, 2H), 7.57 (m, 2H), 7.21 (m, 2H), 2.85 (m, 4H), 2.34 (m, 4H) 2.15 (s, 3H). ESHRMS 398.0993 (M+H, C₁₉H₂₁BrN₅ requires 398.0980).

EXAMPLE 49

The product from Example 2 (50 g, 0.156 mol) and anhydrous hydrazine (25 mL, 0.8 mol) were heated to reflux in ethanol for 5 hours. The contents were allowed to cool whereupon a precipitate formed that was isolated by filtration. The solid was air dried to afford the desired product as a yellow-orange solid (21.8 g) The filtrate was diluted with water (200 mL) and a second crop was obtained as a yellow-orange solid (18.0 g). The pH of the filtrate was adjusted to pH 8 with 3N HCl and the precipitated solid filtered to give an additional crop of the desired product as a yellow-orange solid (2.0 g). The combined crops afforded the desired pyrazole in 93% yield, mp 266.3-268.9° C. ¹H NMR (DMSO-d₆) 13.80 (br, 1H); 12.20 (br s, 1H); 8.32 (s, 4H); 7.50-7.30 (m, 4H). ESHRMS m/z 288.0358 (M+H, C₁₄H₁₁ClN₃S requires 288.0362).

Anal. Calc'd for: C₁₄H₁₀ClN₃S (0.4 H₂O): C, 57.01; H, 3.69; N, 14.25. Found: C, 56.95; H, 3.50 N, 14.14.

EXAMPLE 50

The above pyrazole was prepared by the method outlined in Example 49 mp 261.3-263.9° C. ¹H NMR (DMSO-d₆) 11.55 (br s, 1H); 8.25-8.13 (m, 2H); 7.61-7.50 (m, 2H); 7.36-7.20 (m, 2H); 7.19-7.05 (m, 2H); ESHRMS m/z 272.0691 (M+H, C₁₄H₁₁FN₃S requires 272.0657).

Anal. Calc'd for: C₁₄H₁₀FN₃S (0.25 H₂O): C, 60.97; H, 3.84; N, 15.24. Found: C, 61.05; H, 3.64 N, 15.12.

EXAMPLE 51

To the product from Example 49 (100 mg, 0.35 mmol) in methanol (2 mL) was added 0.5 M sodium methoxide (0.7 mL, 0.35 mmol). Contents were stirred for 15 minutes and filtered to remove a precipitate. The filtrate was concentrated in vacuo, dissolved in water and concentrated in vacuo leaving the desired product as a white solid. ¹H NMR (DMSO-d₆) 11.60 (br s, 1H); 8.20 (d, 2H); 7.60-7.50 (m, 2H); 7.40-7.20 (m, 4H).

Anal. Calc'd for: C₁₄H₉ClN₃NaS (2.5 H₂O): C, 47.40; H, 3.98; N, 11.84. Found: C, 47.39; H, 3.33; N, 11.50.

EXAMPLE 52

To the material prepared in Example 49 (584 mg, 2.0 mmol) and bromoacetonitrile (140 ul, 2.0 mmol) in DMF (5 mL) was added anhydrous potassium carbonate (276 mg, 2.0 mmol). Contents were stirred overnight, then partitioned between EtOAc and H₂O. The EtOAc layer was dried over MgSO₄ and concentrated in vacuo leaving a tan solid. The solid was triturated with MeOH and filtered to give the desired product as a off-white solid, 369 mg, 56%, mp 230.0-230.5° C. ¹H NMR (DMSO-d₆) 13.90 (br s, 1H); 8.58 (d, 2H); 7.60-7.13 (m, 6H); 4.10 (s, 2H). ESHRMS m/z 327.0482 (M+H, C₁₆H₁₂ClN₄S requires 327.0471).

Anal. Calc'd for: C₁₆H₁₁ClN₄S(0.3 H₂O): C, 57.85, H, 3.52; N, 16.87. Found: C, 57.88; H, 3.31; N, 16.77.

EXAMPLE 53

Prepared by the method described in Example 52, using methyl chloroacetate. When the contents were partitioned between EtOAc and H₂O, an insoluble solid was filtered to give the desired product as a white solid 2.16 g. A second crop, 1.68 g, of the desired product gave a total yield of 61%, mp 192.8-195.2° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 9.80 (d, 2H); 7.80 (d, 2H); 7.52-7.34 (m, 4H); 3.92 (s, 2H); 3.57 (s, 3H). ESHRMS m/z 360.05735 (M+H, C₁₇H₁₅ClN₃O₂ requires 360.05732).

Anal. Calc'd for: C₁₇H₁₄ClN₃O₂ (0.25 H₂O): C, 56.05, H, 4.01; N, 11.53. Found: C, 56.10; H, 3.72; N, 11.51.

EXAMPLE 54

The above compound was prepared by heating the product of Example 49 (1.2 g, 4.2 mmol), potassium carbonate (630 mg, 4.6 mmol), N-boc-4-bromopiperidine (1.2 g, 4.5 mmol) were heated in DMF (15 mL) at 105 C for 3 hours. Contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried over MgSO₄and concentrated in vacuo. The residue was triturated with EtOAc and filtered to give the desired as a white solid 1.20 g, 61%, mp 220.9-221.0° C. ¹H NMR (DMSO-d₆) 13.70 (br, 1H); 8.60-8.50 (m, 2H); 7.58-7.10 (m, 6H); 3.80-360 (m, 2H); 3.40-3.20 (m, 1H); 3.00-2.63 (m, 2H); 2.00-1.53 (m, 2H); 1.50-1.05 (m, 2H); 1.40 (s, 9H). FABHRMS m/z 471.1605 (M+H, C₂₄H₂₈ClN₄OS requires 471.1622).

Anal. Calc'd for: C₂₄H₂₇ClN₄OS (0.5 H₂O): C, 60.05; H, 5.88; N, 11.67. Found: C, 60.04; H, 5.57; N, 11.31.

EXAMPLE 55

The product from Example 54 (5.0 g, 11 mmol), and TFA (30 mL) were mixed in CH₂Cl₂ (50 mL) and stirred overnight. Contents were concentrated in vacuo leaving a pale yellow oil which was dissolved in water. The pH was adjusted with 2.5 N NaOH to pH 9, causing a white solid to form that was isolated by filtration to provide the desired product as a white solid, 3.7 g, 93%, mp 211.1-211.2° C. ¹H NMR (DMSO-d₆) 13.80 (br, 1H); 8.55 (d, 2H); 8.40 (br, 1H); 7.50-7.15 (m, 6H); 3.50-3.00 (m, 3H); 3.00-2.80 (m, 2H); 2.05-1.80 (m, 2H); 1.65-1.42 (m, 2H). ESHRMS m/z 371.1103 (M+H, C₁₉H₂₀ClN₄S requires 371.1097).

Anal. Calc'd for: C₁₉H₁₉ClN₄S (H₂O): C, 58.68; H, 5.44; N, 14.41. Found: C, 58.86; H, 5.28; N, 14.25.

EXAMPLE 56

To 1-(2-chloroethyl)pyrrolidine hydrochloride (306 mg, 1.8 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide (7.0 mL, 3.6 mmol). Contents were stirred 10 minutes and then the material from Example 49 (500 mg, 1.8 mmol) were added. Contents were heated to reflux 1 hour, allowed to cool and partitioned between EtOAc and H₂O. The EtOAc layer was dried over MgSO₄ and concentrated in vacuo leaving a light amber solid. The solid was recrystallized from MeOH (15 mL) to give the desired product as a white solid (213 mg, 33% yield). mp 189.9-190.1° C. ¹H NMR (DMSO-d₆) 13.65 (br, 1H); 8.52 (d, 2H); 7.42 (d, 2H); 7.38-7.10 (m, 4H); 3.10-2.93 (m, 2H); 2.63-2.51 (m, 2H); 2.38 (br s, 4H); 1.70-1.52 (m, 4H). ESHRMS m/z 385.1262 (M+H, C₂₀H₂₂ClN₄ requires 385.1254).

Anal. Calc'd for: C₂₀H₂₁ClN₄: C, 62.41, H, 5.50; N, 14.56. Found C, 62.22; H, 5.62; N, 14.48.

EXAMPLE 57

Method A

The material prepared in Example 53 (1.3 g, 3.6 mmol) in methanol (10 mL), 2.5N sodium hydroxide (4 mL) and water (10 mL) were stirred overnight. The contents were concentrated in vacuo to remove the methanol and the aqueous solution left was made acidic to pH 6 with 3N HCl, precipitating a solid. The solid was extracted into EtOAc, dried over MgSO₄ and concentrated in vacuo leaving light tan crystals, 205 mg. Brine was added to the aqueous layer precipitating additional solid that was. filtered to give more desired product as a light tan powder, 529 mg, the total yield was 61%. ¹H NMR (DMSO-d6+10%TFA) 8.80 (d, 2H); 7.83 (d, 2H); 7.55-7.35 (m, 4H); 3.87 (s, 2H).

Method B

The product from Example 53 (3.8 g, 11 mmol) and 3N HCl (30 mL) were heated to reflux for 3 hours. Contents were allowed to cool and concentrated in vacuo. The residue was mixed with CH₃CN (50 mL). Upon standing overnight, pale yellow crystals grew that were isolated by filtration to afford the desired product as the HCl salt 2.9 g, 69%. ¹H NMR (DMSO-d₆) 8.79 (d, 2H); 7.75 (d,

2H); 7.51-7.38 (m, 4H); 3.88 (s, 2H). ESHRMS m/z 346.0435 (M+H, C₁₇H₁₃ClN₄OS requires 346.0417).

Anal. Calc'd for: C₁₇H₁₂ClN₄OS (HCl, 0.5 H₂O): C, 49.12; H, 3.61; N, 10.74. Found: C, 49.36; H, 3.48; N, 10.72.

EXAMPLE 58

The material prepared in Example 53 (400 mg, 11 mmol) and a 2M solution of methylamine in THF (25 mL) were heated to reflux for 3 hours. The reaction was stirred overnight at room temperature and then filtered to afford the desired product as a light amber solid, 335 mg, 85%, mp 284.0-288.4° C. ¹H NMR (DMSO-d₆) 13.58 (br, 1H); 8.60-8.45 (m, 2H); 7.98 (br s, 1H); 7.55-7.12 (m, 6H); 3.60 (2H); 2.46 (s, 3H). ESHRMS m/z 359.0733 (M+H, C₁₇H₁₆ClN₄OS requires 359.0745).

Anal. Calc'd for: C₁₇H₁₅ClN₄OS: C, 56.90; H, 4.21; N, 15.61. Found: C, 56.74; H, 4.11; N, 15.17.

EXAMPLE 59

The material prepared in Example 53 (415 mg, 12 mmol) and N, N-dimethylaminopropylamine were heated to reflux in methanol (25 mL) for 3 hours. The contents were stirred overnight at room temperature and then concentrated in vacuo to afford a solid. The solid was triturated with EtOAc and filtered to give the desired product as a white solid. 256 mg, 50%, mp 168.8-169.5° C. ¹H NMR (DMSO-d₆) 13.80 (br, 1H); 8.55-8.50 (m 2H); 8.02 (t, 1H); 7.50-7.40 (m, 6H); 3.61 (s, 2H); 3.30-2.98 (m, 2H); 2.14-2.10 (m, 2H); 2.04 (s, 6H); 1.50-1.40 (m, 2H). FABHRMS m/z 430.1472 (M+H, C₂₁H₂₅ClN₅OS requires 430.1468).

Anal. Calc'd for: C₂₁H₂₄ClN₅OS (0.5 H₂O ): C, 57.46; H, 5.74; N, 15.95. Found: C, 57.71; H, 5.56; N, 16.12.

EXAMPLE 60

To the material prepared in Example 54 (1.0 g, 2.1 mmol) in CH₂Cl₂ (25 mL) was added 3-chloroperbenzoic acid (425 mg, 2.1 mmol). The reaction was stirred 15 minutes and then chromatographed on silica gel (20 g) eluting with EtOAc. The desired product crystallized from the collected fractions and the product was isolated by filtration and air dried to give 958 mg, 93% mp 215.8-215.9° C. ¹H NMR (DMSO-d₆) 14.34 (br s, 1H); 8.57-8.54 (m, 2H); 7.51-7.25 (m, 6H); 4.00-3.82 (m, 2H); 3.60-3.40 (m, 1H); 2.85-2.70 (m, 2H); 2.10-1.95 (m, 1H); 1.56-1.10 (m, 3H); 1.36 (s, 9H). ESHRMS m/z 487.1580 (M+H, C₂₄H₂₈ClN₄O₃S requires 487.1571).

Anal. Calc'd for: C₂₄H₂₇ClN₄O₃S: C, 59.19; H, 5.59; N, 11.50. Found: C, 59.00; H, 5.76; N, 11.46.

EXAMPLE 61

To the material prepared in Example 60 (320 mg, 0.68 mmol) in EtOH (5 mL) was added an aqueous solution of potassium peroxymonosulfate (420 mg, 0.68 mmol). Contents were stirred for 2 hours and extracted into EtOAc. The extracts were dried over MgSO₄ and concentrated in vacuo leaving a white solid. The solid was triturated with methanol and filtered to give the desired as a white solid, 90 mg, 26%, mp 228.0-230.8° C. ¹H NMR (DMSO-d₆) 8.61 (d, 2H); 7.48 (d, 2H); 7.31-7.20 (m, 4H); 4.05-3.90 (m, 2H); 3.54-3.35 (m, 1H); 2.85-2.60 (m, 2H); 1.92-180 (m, 2H); 1.48-1.25 (m, 2H); 1.32 (s, 9H). ESHRMS m/z 503.1541 (M+H, C₂₄H₂₈ClN₄O₄S requires 503.1520).

Anal. Calc'd for: C₂₄H₂₇ClN₄ _(O) ₄S (H₂O): C, 56.30; H, 5.51; N, 10.94. Found: C, 56.41; H, 5.78; N, 10.54.

EXAMPLE 62

The product from Example 48 was converted to the corresponding sulfoxide by the procedure described Example 60. The crude product was purified by flash chromatography, the solid thus obtained was recrystallized from acetonitrile to give the desired product as white crystals, 64 mg, 33%, mp 189.5-189.5° C. ¹H NMR (DMSO-d₆) 14.28 (br s, 1H); 8.50 (d, 2H); 7.40-7.20 (m, 4H); 7.20-7.05 (m, 4H); 6.85 (d, 2H); 4.41 (s, 2H); 3.70 (s, 3H). ESHRMS m/z 408.1168 (M+H, C₂₂H₁₉FN₃O₂S requires 408.1182).

Anal. Calc'd for: C₂₂H₁₈FN₃O₂S: C, 64.85; H, 4.45; N, 10.31. Found: C, 64.44; H, 4.34; N, 10.70

EXAMPLE 63

To the material prepared in Example 62 (1.2 g, 2.5 mmol) in CH₂Cl₂ (50 mL) was added 3-chloroperbenzoic acid (1.0 g, 5.0 mmol). Contents were stirred 1.5 hours and then filtered to remove a white solid (620 mg). The filtrate was concentrated and the residue chromatographed on silica gel (20 g) eluting with EtOAc to give the desired product as a white solid, 98 mg, 9%, mp 241.9-242.0° C. ¹H NMR (DMSO-d₆) 8.48-8.40 (m, 2H); 7.33-6.80 (m, 10H); 4.55 (s, 2H); 3.72 (s, 3H). ESHRMS m/z 424.1143 (M+H, C₂₂H₁₉FN₃O₃S requires 424.1131).

Anal. Calc'd for: C₂₂H₁₈FN₃O₃S: C, 62.40; H, 4.28; N, 9.92. Found: C, 62.14; H, 4.42; N, 9.68.

EXAMPLE 64

The product from Example 54 (5.0 g, 0.01 mol) and formic acid (96%, 7 mL) were heated at 100° C. for 1 hour. Contents were allowed to cool to about 50° C. and added formaldehyde (37%, 13 mL). The reaction was heated at 80° C. for an additional 2 hours, and then allowed to cool, diluted with water (200 mL) and made basic to pH 11 with 2.5N NaOH whereupon a precipitate formed. The solid was isolated by filtration and recrystallized from methanol to give the desired product as a white solid, 174 mg, 33%, mp 227.7-227.7° C. ¹H NMR (DMSO-d₆) 13.70 (br s, 1H); 8.56-8.48 (m, 2H); 7.50-7.15 (m, 6H); 3.10-2.92 (m, 1H); 2.63-2.50 (m, 2H); 2.05 (s, 3H); 1.95-1.65 (m, 4H); 1.50-1.30 (m, 2H). ESHRMS m/z 385.1233 (M+H, C₂₀H₂₂ClN₄S requires 385.1254).

Anal. Calc'd for: C₂₀H₂₁ClN₄S: C, 62.41; H, 5.50; N, 14.56. Found: C, 62.40; H, 5.80; N, 14.61.

EXAMPLE 65

The above compound was prepared from Example 49 according to the procedure described in Example 54 using bromoethyl methyl ether except that the contents were heated at 70° C. for 1 hour before partitioning between EtOAc and H₂O. The crude was recrystallized from MeOH/EtOAc to give the desired product as a white solid, 210 mg, 35%, mp 189.2-190.2° C. ¹H NMR (DMSO-d₆) 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 3.60-2.85 (m, 7H). ESHRMS m/z 346.0799) M+H, C₁₇H₁₇ClN₃OS requires 346.0781).

Anal. Calc'd for: C₁₇H₁₆ClN₃OS (H₂O): C, 58.73; H, 4.70; N, 12.09. Found: C, 58.67; H, 4.86; N, 12.03.

EXAMPLE 66

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 2-chloromethylbenzimidazole except that the contents were heated at 70° C. for 1 hour before partitioning between EtOAc and H₂O. An insoluble solid was filtered from the two layers and triturated with MeOH to give the desired product as a light amber solid, 292 mg, 40%, mp 257.7-257.7° C. ¹H NMR (DMSO-d₆) 13.75 (br s, 1H); 12.30 (br s, 1H); 8.55-8.30 (m, 2H); 7.65-6.90 (m, 10H); 4.40 (br s, 2H). FABHRMS mz 418.0895 (M+H, C₂₂H₁₇ClN₅ requires 418.0893).

Anal. Calc'd for: C₂₂H₁₆ClN₅ (0.75 H₂O): C, 61.25; H, 4.09; N, 16.23. Found: C, 61.27; H, 3.90; N, 15.92.

EXAMPLE 67

The above compound was prepared from Example 49 according to the procedure described in Example 54 using D,L-alpha-bromo-beta-(4-imidazolyl)propionic acid except that the contents were heated at 70° C. for 1 hour. The contents contained an insoluble solid which was diluted with water and the pH was adjusted with 3N HCl to pH 7. Contents were filtered and triturated with MeOH to give the desired product as a white solid, 15 g, 81%, mp 163.0-165.5° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.92 (d, 1H); 8.83-8.75 (m, 2H); 7.80 (d, 2H); 7.55-7.30 (m, 5H); 4.20-4.05 (m, 1H); 3.25-3.00 (m, 2H). ESHRMS m/z 426.0799 (M+H, C₂₀H₁₇ClN₅O₂S requires 426.0791).

Anal. Calc'd for: C₂₀H₁₆ClN₅O₂S (1.8 H₂O): C, 52.41 H, 4.31; N, 15.28. Found: C, 52.68; H, 4.58; N, 15.37.

EXAMPLE 68

The above compound was prepared from Example 49 (264 mg, 0.9 mmol) according to the procedure described in Example 54 and alpha-methylenebutyrolactone (0.08 mL, 0.9 mmol) in EtOH was added a drop of triethylamine. Contents were stirred overnight and the resulting solid was filtered and triturated with MeOH to give the desired product as a pale yellow solid, 181 mg, 51%, mp 224.2-225.9° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.53-7.33 (m, 4H); 4.30-4.05 (m, 2H); 3.50-3.40 (m, 1H); 3.15-2.90 (m, 2H); 2.32-2.20 (m, 1H) 2.10-1.90 (m, 1H). ESHRMS m/z 386.0760 (M+H, C₁₉H₁₇ClN₃O₂S requires 386.0730).

Anal. Calc'd for: C₁₉H₁₆ClN₃O₂S: C, 59.14 H, 4.18; N, 10.89. Found: C, 58.97; H, 4.21; N, 10.96.

EXAMPLE 69

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 2-bromomethyl-1,3-dioxolane except that the contents were heated at 80° C. for 2 hours. The reaction was diluted with water and filtered to give a white solid, 502 mg. The solid was recrystallized from EtOH to give the desired product as off-white crystals, 280 mg, 43%, mp 197.0-198.2° C. ¹H NMR (DMSO-d₆) 13.60 (br s, 1H); 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 5.15-4.85 (m, 1H); 3.95-3.62 (m, 4H); 3.40-2.95 (m, 2H). ESHRMS m/z 374.0741 (M+H, C₁₈H₁₇ClN₃O₂S requires 374.0730).

Anal. Calc'd for: C₁₈H₁₆ClN₃O₂S: C, 57.83 H, 4.31; N, 11.24. Found: C, 57.69; H, 4.41., N, 11.15.

EXAMPLE 70

The above compound was prepared from Example 53 according to the procedure described in Example 54 using 2-(2-bromoethoxy)tetrahydro-2H-pyran except that the contents were heated at 80° C. for 4 hours. Contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried over MgSO₄ and concentrated in vacuo leaving a solid, 737 mg. The solid was recrystallized from EtOH to give the desired product as pale yellow crystals, 281 mg, 39%, mp 163.2-163.5° C. ¹H NMR (DMSO-d₆) 13.80-13.70 (m, 1H), 8.60-8.42 (br s, 1H); 7.60-7.10 (m, 6H); 4.60-4.30 (m, 1H); 3.90-2.90 (m, 6H); 1.70-1.20 (m, 6H). ESHRMS m/z 416.1200 (M+H, C₂₁H₂₃ClN₃O₂S requires 416.1198).

Anal. Calc'd for: C₂₁H₂₂ClN₃O₂S: C, 60.64 H, 5.33; N, 10.10. Found: C, 60.49; H, 5.71; N, 9.96.

EXAMPLE 71

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 4-bromobutyronitrile except that the contents were heated at 55° C. for 1 hour. Contents were diluted with water (75 mL) and filtered to give a white solid, 567 mg. The solid was recrystallized from MeOH to give the desired product as white crystals, 333 mg, 54%, mp 216.7-216.9° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.80-8.75 (m, 2H); 7.83-7.75 (m, 2H); 7.50-7.35 (m, 4H); 3.10-3.00 (m, 2H); 2.60-2.45 (m, 2H); 1.95-1.80 (m, 2H). ESHRMS m/z 355.0818 (M+H, C₁₈H₁₆ClN₄S C₁₈H₁₆ClN₄S requires 355.0784).

Anal. Calc'd for: C₁₈H₁₅ClN₄S(0.5 H₂O): C, 59.42 H, 4.43; N, 15.40. Found: C, 59.64; H, 4.11; N, 15.44.

EXAMPLE 72

The product from Example 57 (416 mg, 1.1 mmol), morpholine (4 mL), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (481 mg, 1.5 mmol) and DMF (10 HL) were stirred at room temperature overnight. The reaction mixture was diluted with water (75 mL) and the resulting solid isolated by filtration, 363 mg. The crude product was recrystallized from EtOH to give the desired product as a white solid, 219 mg, 48%, mp 215.4-215.5° C. ¹H NMR (DMSO-d₆) 13.70-13.60 (m, 1H); 8.60-8.50 (m, 2H); 7.50-7.10 (m, 6H); 3.93-3.80 (m, 2H); 3.60-3.20 (m, 8H). ESHRMS m/z 415.0995 (M+H, C₂₀H₂₀ClN₄O₂S requires 415.1001).

Anal. Calc'd for: C₂₀H₁₉ClN₄O₂S: C, 57.90 H, 4.62; N, 13.50. Found: C, 57.87; H, 4.86; N, 13.53.

EXAMPLE 73

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 2-bromopropionitrile except that the reaction was heated at 70° C. for 1 hour.

The reaction solution was diluted with water (75 mL) and filtered to give an off-white solid, 662 mg. The crude product was recrystallized from MeOH to give the desired product as a white solid, 220 mg, 37%, mp 211.1-212.8° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.87-8.80 (m, 2H); 7.90-7.80 (m, 2H); 7.55-7.45 (m, 6H); 4.42 (q, 1H); 1.50 (d, 3H). ESHRMS m/z 341.0628 (M+H, C₁₈H₁₄ClN₄S requires 341.0628).

Anal. Calc'd for: C₁₈H₁₃ClN₄S: C, 59.91 H, 3.84; N, 16.44. Found: C, 59.64; H, 4.01; N, 16.18.

EXAMPLE 74

The above compound was prepared from Example 49 according to the procedure described in Example 54 using propargyl bromide. The reaction mixture was diluted with water (75 mL) and filtered to give a pale yellow solid, 577 mg. The solid was triturated with MeOH to give the desired product as a white solid, 388 mg, 68%, mp 212.7-213.2° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.80 (d, J=6.8 Hz, 2H); 7.82 (d, J=6.8 Hz, 2H); 7.50-7.35 (m, 4H); 3.81 (d, J=2.6 Hz, 2H); 3.05 (t, J=2.6 Hz, 1H). ESHRMS m/z 326.0533 (M+H, C₁₇H₁₃ClN₃S requires 326.0519).

Anal. Calc'd for: C₁₇H₁₂ClN₃S (0.2 H₂O): C, 61.98 H, 3.79; N, 12.76. Found: C, 61.89; H, 3.45; N, 12.67.

EXAMPLE 75

The above compound was prepared from Example 49 according to the procedure described in Example 54 using allyl bromide. The reaction mixture was diluted with water (75 mL) and filtered to give a pale yellow solid, 509 mg. The solid was recrystallized from MeOH to give the desired product as a pale yellow solid, 187 mg, 33%, mp 207.3-208.1° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.50-7.30 (m, 4H); 5.90-5.70 (m, 1H); 5.10-4.95 (m, 2H); 3.62 (d, 2H). ESHRMS m/z 328.0693 (M+H, C₁₇H₁₅ClN₃S requires 328.0675).

Anal. Calc'd for: C₁₇H₁₄ClN₃S (0.1 H₂O): C, 61.94 H, 4.34; N, 12.75. Found: C, 61.83; H, 4.21; N, 12.76.

EXAMPLE 76

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 2-bromoethylamine hydrochloride except that two equivalents of potassium carbonate were used. The reaction mixture was diluted with water (75 mL) and filtered to give a pale yellow solid, 509 mg. The solid was recrystallized from MeOH to give the desired product as a pale yellow solid, 262 mg, 45%, mp 186.8-187.8° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.85-8.75 (m, 2H); 8.90 (br s, 2H); 8.85-8.75 (m, 2H); 7.55-7.35 (m, 4H); 3.30-3.00 (m, 4H). ESHRMS m/z 331.0779 (M+H, C₁₆H₁₆ClN₄S requires 331.0784).

Anal. Calc'd for: C₁₆H₁₅ClN₄S (0.5 H₂O): C, 56.55; H, 4.75; N, 16.49. Found: C, 56.28; H, 4.38; N, 16.20.

EXAMPLE 77

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 3-(2-bromoethyl)indole. The reaction mixture was diluted with water (75 mL) and filtered to give a pale yellow solid, 752 mg. The solid was triturated with MeOH to give the desired product as a white solid, 682 mg, 91%, mp 211.9-213.2° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 10.80 (s, 1H); 8.72 (d, 2H); 7.71 (d, 2H); 7.55-7.35 (m, 5H); 7.29 (d, 1H); 7.12-6.88 (m, 3H); 3.40-3.30 (m, 2H); 3.05-2.95 (m, 2H). ESHRMS m/z 431.1095 (M+H, C₂₄H₂₀ClN₄S requires 431.1097).

Anal. Calc'd for: C₂₄H₁₉ClN₄S(0.15 H₂O): C, 66.47 H, 4.49; N, 12.92. Found: C, 66.44; H, 4.51; N, 12.84.

EXAMPLE 78

The product from Example 60 (464 mg, 0.95 mmol) and TFA (8 mL) were mixed in CH₂Cl₂ (10 mL) and stirred overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and water. The aqueous layer was made basic to pH 10 with 2.5N NaOH and extracted with EtOAc (2×100 mL). Upon standing overnight, a solid precipitated from the aqueous layer and was filtered to give the desired product as a white solid, 183 mg, 50%, mp 189.1-190.8° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.85 (d, 2H); 8.80-8.60 (m 1H); 8.45-8.25 (m, 1H); 7.90 (d, 2H); 7.55-7.30 (m, 4H); 3.65-3.20 (m 3H); 3.10-2.80 (m 2H); 2.20-2.00 (m, 1H); 1.90-1.50 (m, 3H). ESHRMS m/z 387.1032 (M+H, C₁₉H₂₀ClN₄OS requires 187.1046).

Anal. Calc'd for: C₁₉H₁₉ClN₄OS.(2 H₂O): C, 53.96 H, 5.48; N, 13.25. Found: C, 53.75; H. 4.99; N, 13.21.

EXAMPLE 79

The above compound was prepared from Example 49 according to the procedure described in Example 54 using 3-bromopropionitrile. The reaction mixture was diluted with water (75 mL) and extracted into EtOAc, which. was dried over MgSO₄ and concentrated in vacuo leaving an orange waxy solid, 523 mg. The solid was dissolved in acetonitrile, filtered through a pad of silica gel and eluted with EtOAc to give a white solid. The solid was triturated with EtOAc and filtered to give the desired product as a white solid, 76 mg, 13%, mp 205.7-206.5° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.55-7.35 (m, 4H); 3.30-3.20 (m, 2H); 2.90-2.80 (m, 2H). ESHRMS m/z 341.0639 (M+H, C₁₄H₂₀ClN₄S requires 341.0628).

Anal. Calc'd for: C₁₄H₁₃ClN₄S (0.25 H₂O): C, 59.13 H, 3.94; N, 16.22. Found: C, 59.03; H, 3.93; N, 15.90.

EXAMPLE 80

Prepared by the method described in Example 1, steps I and 2. mp 168.6-168.7° C. ¹H NMR (CDCl₃/300 MHz) 8.54 (dd, 2H, J=4.6, 1.8 Hz), 7.68-7.62 (m 2H), 7.43-7.39 (m, 1H), 7.33-7.28 (m, 1H), 6.99 (dd, 2H, J=4.4, 1.6 Hz), 4.22 (s, 2H). ESHRMS m/z 311.0330 (M+H, C₁₆H₁₀N₂OS₂ requires 311.0313).

Anal. Calc'd. for C₁₆H₁₀N₂OS₂: C, 61.91; H, 3.25; N, 9.02. Found: C, 61.45; H, 3.18; N, 8.91.

EXAMPLE 81

2-(4-flourophenyl)-4-methythiophenylethanone (1.26 g, 4.84 mmol), potassium carbonate (2.04 g 14.5 mmol), carbon disulfide (1.10 g, 14.5 mmol) and dibromomethane (1.10 g, 15.4 mmol) were mixed together in acetone (50 ml) for 12 days. The solution was poured into ethyl acetate (100 mL) and washed with 1N hydrochloric acid. Hexanes (25 mL) were added and the solution was washed with brine (2×100 mL). The organic solution was collected, dried over sodium sulfate and solvent removed at reduced pressure. The product 1 was isolated by crystallization from ethyl acetate and hexanes. 831 mg of yellow crystals were obtained. (49% yield) mp 145.7-145.7° C. ¹H NMR (CDCl₃/300 MHz) 7.19-7.24 (m, 2H), 7.06-7.11 (m, 2H), 6.60-7.30 (m, 4H), 4.11 (s, 2H), 2.42 (s, 3H). HRMS 349.0201 (M+H calcd for C₁₇H₁₄FOS₃ 349.0191).

The dithiatane (613 mg, 1.76 mmol) and anhydrous hydrazine (300 uL) were refluxed in ethanol (10 mL) for 16 hours. The solution was cooled to room temperature and poured into ethyl acetate (50 mL). The solution was extracted with 1 N hydrochloric acid (2×25 mL). Hexanes (10 mL) were added and the solution was extracted with brine (2×25 mL), dried over sodium sulfate, and solvent removed at reduced pressure. The product 2 was isolated by crystallization from dichloromethane and hexanes. 186 mg of yellow crystals were obtained. (32% yield) mp 142.4-143.4° C. ¹H NMR (CD₃OD/400 MHz) 7.18-7.27 (m, 6H), 7.06-7.10 (m,3H), 2.43 (s, 3H). HRMS 317.0586 (M+H, calcd for C₁₆H₁₄FN₂S₂ 317.0582)

The pyrazole 2 (140 mg, 0.44 mmol), potassium carbonate (150 mg, 106 mmol) and iodomethane (71 mg, 0.50 mmol) were stirred in dimethylformamide (5 mL) at room temperature for 16 h. The solution as poured into ethyl acetate (40 mL) and washed with 1N hydrochloric acid (2×40 mL). Hexanes (25 mL) were added and the solution was washed with brine (2×50 mL). The organic solution was collected, dried over sodium sulfate and solvent removed at reduced pressure. The product (22 mg) was isolated as a semi solid by preparative thin layer chromatography. (13% yield) ¹H NMR (CDCl₃/400 MHz) 7.23-7.27 (m, 2H), 7.14-7.22 (m, 2H), 2.46 (s, 3H), 2.41 (s, 3H). HRMS 331.0735 (M+H, C₁₇H₁₆FN₂S₂ calcd for 331.0739).

EXAMPLE 82

Step 1

Preparation of 1-(4-chlorophenyl)-2-(4-pyrimidyl)ethanone

Lithium bis(trimethylsilyl)amide 1.0 M in THF (4.25 L, 4.25 mol) was cooled to −70° C. with stirring under nitrogen. 4-methylpyrimidine (250 g, 2.66 mol) was added followed by Methyl 4-chlorobenzoate (453.2 g, 2.66 mol). The cooling bath was removed and the mixture was allowed to warm to room temperature and stir for 16 h. Water (3 L) and ethyl acetate (3 L) were added followed by acetic acid (200 mL). The layers were separated and the organic layer was washed with brine and dried over magnesium sulfate. The mixture was then concentrated to 800 mL and hexanes (250 mL) were added. The product was filtered, washed with hexanes, and air dried to provide a yellow solid. (388.1 g, 64%): mp 110.4-110.5° C. ¹H NMR (acetone-d₆/300 MHz) 14.9 (bs, 1H), 8.8 (s, 1H), 8.4 (m, 1H), 7.7 (d, 2H, J=8.7 Hz), 7.3 (d, 2H, J=8.7 Hz), 6.9 (m, 1H), 5.9 (s, 1H).

Step 2

Preparation of Dithietane Compound

To a solution of 1-(4-chlorophenyl)-2-(4-pyrimidyl)ethanone (7.0 g, 0.03 mol) in a mixture of acetone (200 mL) and dibromomethane (75 mL) was added potassium carbonate (8.3 g, 0.06 mol), followed by the slow addition of carbon disulfide (2.6 g, 0.033 mol) over 15 minutes. The reaction mixture was stirred at room temperature for 20 h. Solvent was removed and the residue was partitioned between water and methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and triturated with a mixture of ethyl acetate/ether/hexane (1:5:5) to give 7.14 g of product as a yellow solid which was used without further purification in the next step.

Step 3

Preparation of 1-[5-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-pyrazol-3-yl-3,4-dimethylpiperazine

To a suspension of the crude material from Step 2 (4.0 g, 0.013 mol) in 30 mL of toluene was added a solution of 2,6-dimethylpiperazine (4.65 g, 0.04 mol) in 3 mL of acetonitrile. The reaction mixture was stirred at 85° C. for 4 h. After the removal of solvent, the crude material was dissolved in 100 mL of dry THF and hydrazine (0.83 g, 0.026 mol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under vacuum and the residue was purified by chromatography in silica gel (ethyl acetate/methanol, 3:1 to 1:1) to afford 0.75 g of the product as a white solid (13% overall yield), mp: 212-214° C.;

Anal. Calcd. for C₁₉H₂₁ClN₆: C, 61.87; H, 5.74; N, 22.78. Found: C, 61.59; H, 5.28; N, 22.28.

EXAMPLE 83

A mixture of the dithietane compound from example 2 (6.4 g, 0.02 mol) and 2,6-dimethylpiperazine (6.86 g, 0.06 mol) in 100 mL of toluene was heated at reflux for 2 h. Solvent and excess 2,6-dimethylpiperazine was removed under vacuum and the crude was used without purification. A solution of the above crude and anhydrous hydrazine (1.3 g, 0.04 mol) in 100 mL of dry THF was stirred at room temperature overnight. After the removal of THF, the residue was stirred with a mixture of ethyl acetate (100 mL) and ammonia hydroxide (20 mL) for 1 h. The precipitate was filtered and air-dried to give 3.4 g of product as a white solid (46% overall yield), mp: 236-238° C.; Anal. Calcd. for C₂₀H₂₂ClN₅+0.25 H₂O: C, 64.51; H, 6.09; N, 18.81; Cl, 9.52. Found: C, 64.28; H, 5.85; N, 18.70; Cl, 9.67.

EXAMPLE 84

Prepared by the method described in Example 1, step 1, using 4-methylpyrimidine in place of 4-picoline. ¹H NMR (CDCl₃+TFA/300 MHz) 8.96 (s, 1H), 8.10 (d, 1H), 7.88 (d, 2H), 7.36 (d, 2H), 7.09 (d, 1H), 6.43 (s, 1H), 2.48 (s, 3H). ESHRM m/z 213.1003 (M+H, C₁₃H₁₂N₂O requires 213.1027).

Anal. Calc'd. for C₁₃H₁₂N₂O: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.41; H, 6.04; N, 13.17.

EXAMPLE 85

Prepared by the method described in Example 1, step 2.

¹H NMR (CDCl₃/300 MHz) 9.02 (s, 1H), 8.40 (d, 1H), 7.37 (d, 2H), 7.23 (d, 2H), 6.67 (d, 1H), 4.24 (s, 2H), 2.33 (s, 3H). ESHRMS m/z 301.0488 (M+H, C₁₅H₁₂N₂OS₂ requires 301.0469).

Anal. Calc'd. for C₁₅H₁₂N₂OS₂: C, 59.97; H, 4.03; N, 9.33. Found: C, 59.43; H, 3.86; N, 9.14.

EXAMPLE 86

The product was prepared in an analogous manner to that of Example 32, starting with 4-hydroxy-N-t-boc piperidine and the product of Example B.

¹H NMR (DMSO-d₆/300 MHz) 8.85 (s, 1H), 8.66 (d, 1H), 7.68 (d, 1H), 7.37 (d, 2H), 7.22 (d, 2H), 4.94 (m, 1H), 3.58 (m, 2H), 2.34 (s, 3H), 1.97 (m, 2H), 1.69 (m, 2H), 1.40 (s, 9H). ESHRMS m/z 436.2364 (M+H, C₂₄H₂₉N₅O₃ requires 436.2348).

Anal. Calc'd. for C₂₄H₂₉N₅O₃.0.7 H₂O: C, 64.33; H, 6.84; N, 15.63. Found: C, 64.40; H, 6.79; N, 15.63.

The following abbreviations have the indicated meanings:

Ac=acetyl

Boc=tertiary-butyloxycarbonyl

CDCl₃=Chloroform-d

DMAP=4-(dimethylamino)pyridine

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc=ethyl acetate

EtOH=ethanol

ESHRMS=electro-spray high resolution mass spectrum

ESLRMS=electro-spray low resolution mass spectrum

FABHRMS=fast atom bombardment high resolution mass spectrum

HCl=Hydrochloric Acid

H₂O=water

HOBt=1-hydroxybenzotriazole

KHMDS=Postassium bis(trimethylsilyl)amide

MeOH=methanol

MgSO₄=magnesium sulfate

NaCl=Sodium Chloride

NaHMDS=Sodium bis(trimethylsilyl)amide

NaOH=Sodium Hydroxide

NMR=nuclear magnetic resonance spectroscopy

TBTU=O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium terafluoroborate

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=Thin Layer Chromatography

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

We claim:
 1. The process of making compounds of Formula IIIa or IIIb

wherein: R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6 membered heterocycle substituted with one or more of the substituents selected from the group consisting of alkyl, halo, OH, O-alkyl, cyano, CF₃, OCF₃, and substituted phenyl wherein the substituents are selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, SO₂CH₃ SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl, alkenyl, and alkynyl; R₂ is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of one or more hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenyl substituted from the group selected from hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino, and dialkylamino; R₃ is selected from the group selected from hydrogen, alkyl, phenyl of which all but hydrogen may be optionally substituted by one or more of the group consisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, and SO₂NH₂; R₆ is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally substituted by one or more of the group consisting of phenyl, substituted phenyl, halo, alkoxycarbonyl, acyl, OH, NH₂, NHR₃, N(R₃)₂, and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring; comprising: reacting an organometallic reagent of the formula R₂CH₂M wherein M is selected from the group consisting of Li, Na, K, and Mg, with an activated form of a carboxylic acid to produce a ketone of Formula IIIc;

treating the ketone of Formula IIIc with a mixture of carbon disulfide and dihalomethane in the presence of a base and a solvent to produce the dithietane derivative of Formula IIId;

reacting the dithietane derivative of Formula IIId with R₃NHNH₂ to produce a heterocycle of the formula IIIe or IIIf and their tautomers;

reacting the heterocycle of the formula IIIe or IIIf with an activated form of R₆ in the presence of a base and a solvent.
 2. The process of claim 1 wherein: R₁ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, OC₁₋₆ alkyl, OC₃₋₆ cycloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, and 5 or 6 membered heterocycle substituted with one or more of the substituents selected from the group consisting of C₁₋₃ alkyl, halo, OH, OC₁₋₃ alkyl, cyano, CF₃, OCF₃, and substituted phenyl wherein the substituents are selected from the group consisting of hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, cyano, CF₃, OCF₃, C₁₋₃ alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOC₁₋₄ alkyl, SO₂NHCOC₁₋₄ alkyl, C₁₋₄ alkenyl, and C₁₋₄ alkynyl; R₂ is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C₁₋₆ alky, mono- or di-substituted 6-membered heterocycle wherein the substituent is selected from the group consisting of one or more hydrogen, halo, OC₁₋₆ alkyl, SC₁₋₆ alkyl, cyano, CF₃, OCF₃, C₁₋₆ alky, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, and mono or di-substituted phenyl optionally substituted from the group selected from hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkylthio, cyano, CF₃, OCF₃, C₁₋₆ alkyl, C₁₋₆ alkylamino, and C₁₋₆ dialkylamino; R₃ is selected from the group selected from hydrogen, C₁₋₆ alkyl, and phenyl of which all but hydrogen may be optionally substituted by one or more of the group consisting of SO₂CH₃, halo, C₁₋₃ alkyl, OC₁₋₃ alkyl, SC₁₋₃ allyl, cyano, CF₃, OCF₃, and SO₂NH₂; R₆ is selected from the group consisting of hydrogen, C₁₋₆ alkyl which may be optionally substituted by one or more of the group consisting of phenyl, substituted phenyl, halo, OH, NH₂, NHR₃, N(R₃)₂, and cyano, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, and 3-7 membered heterocycle ring.
 3. The process of claims 1 or 2 wherein the dihalomethane is dibromomethane.
 4. The process of claims 1 or 2 wherein the dihalomethane is iodochloromethane. 